Process for production of glucopyranosyloxypyrazole derivative

ABSTRACT

The present invention relates to a method for preparing the glucopyranosyloxypyrazole derivatives which are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, diabetic complications, obesity or the like. A glucopyranosyloxypyrazole derivative can be easily and efficiently prepared by allowing a benzylpyrazole derivative represented by the general formula: 
                         
wherein R 1 , R 2 , R 3 , R 4  and R 5  may be the same or different, for example each of them is a hydrogen atom, a halogen atom or an alkyl, alkoxy, arylmethyloxy group or the like, R 6  is an alkyl group, for example R 7  is a hydrogen atom or an alkyl, alkoxy, arylmethyloxy group or the like, to react with a compound represented by the general formula:
 
                         
wherein as an example, PG 1  is a pivaloyl group or the like, as an example, X 1  is a bromine atom or the like, therefore the present invention is extremely useful as a method for preparing pharmaceutical compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage application of PCT internationalapplication PCT/JP2006/305295, filed Mar. 16, 2006, which claimspriority to foreign application JP2005-076644, filed Mar. 17, 2005 inJapan.

TECHNICAL FIELD

The present invention relates to a method for preparingglucopyranosyloxypyrazole derivatives useful as intermediates formanufacturing medicaments.

More particularly, the present invention relates to a method forpreparing the glucopyranosyloxypyrazole derivatives which are useful asagents for the prevention or treatment of a disease associated withhyperglycemia such as diabetes, diabetic complications, obesity or thelike. For example, the present invention relates to a method forpreparing a glucopyranosyloxypyrazole derivative represented by thegeneral formula:

wherein R¹, R², R³, R⁴ and R⁵ may be the same or different, each of themis a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a haloC₁₋₆ alkylgroup, a C₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyloxy group, a C₃₋₆cycloalkyl (C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, a haloC₁₋₆ alkoxy group, an aryl group, an aryloxy group, aheteroaryl group, an aryl (C₁₋₆ alkyl) group, an aryl (C₁₋₆ alkoxy)group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a heteroC₃₋₆cycloalkyl group, a heteroC₃₋₆ cycloalkyloxy group, a heteroC₃₋₆cycloalkyl(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy group substituted by anamino group which is mono-substituted by a C₁₋₆ alkyl group or a C₁₋₆alkoxy group substituted by an amino group which is di-substituted by aC₁₋₆ alkyl group, R⁶ is a C₁₋₆ alkyl group, a haloC₁₋₆ alkyl group or aC₃₋₆ cycloalkyl group, R¹⁰ is a hydrogen atom, a C₁₋₆ alkyl group, aC₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyl-substituted C₁₋₆ alkyl group,an aryl (C₁₋₆ alkyl) group, a heteroC₃₋₆ cycloalkyl group, a heteroC₃₋₆cycloalkyl (C₁₋₆ alkyl) group or a group forming a prodrug, and Q² is agroup represented by the general formula:

in which P is a hydrogen atom or a group forming a prodrug. As theglucopyranosyloxypyrazole derivative, in addition, for example, PatentReferences 1 to 13 as described below can be illustrated.

BACKGROUND ART

It has been reported that the glucopyranosyloxypyrazole derivativesrepresented by the above general formula (A) are useful as agents forthe prevention or treatment of a disease associated with hyperglycemiasuch as diabetes, diabetic complications, obesity or the like (forexample, see Patent References 1 to 13).

Previously, as the method for preparing the glucopyranosyloxypyrazolederivatives represented by the above general formula (A), glycosylationusing a benzylpyrazole derivative represented by the general formula:

wherein R⁶⁶ is a C₁₋₆ alkyl group, and R¹ and R² have the same meaningsas defined above, and a hydroxy-protected α-D-glucopyranosylhalogenderivative in the presence of silver carbonate or silver oxidecontaining silver that is a heavy metal has been reported (for example,see Patent References 1 to 6).

However, when the glycosylation is carried out for a hydroxy-protectedα-D-glucopyranosylbromide using the pyrazole derivative represented bythe above general formula (II) wherein R⁶⁶ is a lower alkyl group underreported condition, side reactions that the pyrazole derivativerepresented by the above general formula (II) used in the reactionreacts with each other or that a nitrogen atom on the pyrazole ring isglycosylated occur, and the problems could not be avoided. And a problemthat a special purification process to remove those by-products wasneeded existed. Furthermore, conditions to use a strong base or areagent that contains silver that is the heavy metal was examined tosuppress the side reaction. However, when the heavy metal is used forthe manufacturing process of a medicine, a special purification processis necessary so that the heavy metal used does not remain in themedicine, and various analyze characteristics to be inspected to confirmwhether the heavy metal remains in the medicine have to be conducted,therefore, there was a problem that a number of complex workingincreased. Heretofore, it is reported that reaction time becomes long ifsilver is not used, and for example, it requires several days toglycosylate, though other glycosylations without the use of the reagentthat contains silver are examined to solve these problems (see PatentReference 6). On the other hand, though a method by adding aphase-transfer catalyst to shorten the time of the glycosylation is alsoexamined, so this time, various problems such as a problem that largeexcess of a sugar donor is needed, a problem that reactive yield is notconstant, and a problem that conduct on an industrial scale is difficultare caused.

On the other hand, in Patent Reference 14, a method for obtaining a5-thio-D-glucopyranoside derivative represented by the general formula:

by subjecting a pyrazole derivative represented by the general formula:

and 2,3,4,6-tetra-O-acetyl-5-thio-D-glucose represented by a formula:

to Mitsunobu reaction that uses triphenylphosphine anddiisopropylazodicarboxylate is described. However, this reaction isdifferent from the present invention because it is a different product(a 5-thio-D-glucopyranoside derivative) by a different method forpreparing (Mitsunobu reaction) by the use of a different substrate2,3,4,6-tetra-O-acetyl-5-thio-D-glucose. Moreover, in the above PatentReference 14, it is not described that this reaction is applicable tomanufacturing of an α-D-glucopyranosylhalogen derivative. And becausethe α/β selectivity of the product is not excellent, Mitsunobu reactiondescribed in the above Patent Reference 14 has a problem that anotherprocess to remove the product of unnecessary configuration is needed,and unnecessary product should be disposed in economical respect. AndMitsunobu reaction has a problem of generating triphenylphosphine oxidedifficult to remove as a by-product.

As mentioned above, the methods ever reported are not alwayssatisfactory, and the development of a easier and more efficient processof manufacturing has been desired.

-   Patent Reference 1: International Publication WO02/053573 pamphlet;-   Patent Reference 2: International Publication WO01/16147 pamphlet;-   Patent Reference 3: International Publication WO02/068439 pamphlet;-   Patent Reference 4: International Publication WO02/36602 pamphlet;-   Patent Reference 5: International Publication WO02/020737 pamphlet;-   Patent Reference 6: International Publication WO02/088157 pamphlet;-   Patent Reference 7: Japanese Patent Publication 2003-012686;-   Patent Reference 8: International Publication WO2005/021566    pamphlet;-   Patent Reference 9: Japanese Patent Publication 2004-137245;-   Patent Reference 10: International Publication WO02/098893 pamphlet;-   Patent Reference 11: International Publication WO2004/014932    pamphlet;-   Patent Reference 12: International Publication WO2004/018491    pamphlet;-   Patent Reference 13: International Publication WO2004/019958    pamphlet;-   Patent Reference 14: International Publication WO2004/089967    pamphlet.

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The object of the present invention is to provide a method for preparingthe glucopyranosyloxypyrazole derivatives which are useful as agents forthe prevention or treatment of a disease associated with hyperglycemiasuch as diabetes, diabetic complications, obesity or the like. Moreparticularly, it is to provide a novel method for preparing theglucopyranosyl-oxypyrazole derivative represented by the above generalformula (A) or a pharmaceutically acceptable salt thereof.

Means of Solving the Problems

As a result that the present inventors have studied earnestly to solvethe above problem, it was found that the glucopyranosyloxypyrazolederivative represented by the above general formula (A) or apharmaceutically acceptable salt thereof is able to be prepared easilyby allowing a benzylpyrazole derivative represented by the generalformula:

wherein R¹, R², R³, R⁴ and R⁵ may be the same or different, each of themis a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a haloC₁₋₆alkylgroup, a C₃₋₆cycloalkyl group, a C₃₋₆cycloalkyloxy group, a C₃₋₆cycloalkyl (C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthiogroup, a haloC₁₋₆ alkoxy group, an aryl group, an aryloxy group, aheteroaryl group, an aryl (C₁₋₆ alkyl) group, an aryl (C₁₋₆ alkoxy)group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a heteroC₃₋₆cycloalkyl group, a heteroC₃₋₆ cycloalkyloxy group, a heteroC₃₋₆cycloalkyl(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy group substituted by anamino group which is mono-substituted by a C₁₋₆ alkyl group or a C₁₋₆alkoxy group substituted by an amino group which is di-substituted by aC₁₋₆ alkyl group, R⁶ is a C₁₋₆ alkyl group, a haloC₁₋₆ alkyl group or aC₃₋₆ cycloalkyl group, and R⁷ is a hydrogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group or an arylmethyloxy group, to react with anα-D-glucopyranosylhalogen derivative represented by the general formula:

wherein PG¹ is an acetyl group, a pivaloyl group, an arylcarbonyl groupor an arylmethyl group, and X¹ is a bromine atom or a chlorine atom,thereby forming the bases of the present invention.

That is, the present invention relates to a method and the like forpreparing a glucopyranosyloxypyrazole derivative represented by thegeneral formula:

wherein Q¹ is a group represented by the general formula:

in which PG¹ has the same meaning as defined above, R¹, R², R³, R⁴, R⁵,R⁶ and R⁷ have the same meanings as defined above comprising allowing abenzylpyrazole derivative represented by the general formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the same meanings as definedabove to react with an α-D-glucopyranosylhalogen derivative representedby the general formula:

wherein PG¹ is an acetyl group, a pivaloyl group, an arylcarbonyl groupor an arylmethyl group, and X¹ is a bromine atom or chlorine atom.

In the present invention, the following terms have the followingmeanings if not otherwise specified especially.

The term “halogen atom” means a fluorine atom, a chlorine atom, abromine atom or an iodine atom.

The term “C₁₋₆ alkyl group” means a straight-chained or branched alkylgroup having 1 to 6 carbon atoms such as a methyl group, an ethyl group,a propyl group, an isopropyl group, a butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group,a neopentyl group, a tert-pentyl group, a 1-methylbutyl group, a2-methylbutyl group, a hexyl group or the like.

The term “haloC₁₋₆ alkyl group” means the above C₁₋₆ alkyl groupsubstituted by the same or different halogen atom as defined above. Forexample, a trifluoromethyl group, a 1,1,1-trifluoroethyl group, a1,1,2,2-pentafluoroethyl group or the like can be illustrated.

The term “C₃₋₆ cycloalkyl group” means a cyclic alkyl group such as acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup or the like.

The term “C₁₋₆ alkoxy group” means a straight-chained or branched alkoxygroup having 1 to 6 carbon atoms such as a methoxy group, an ethoxygroup, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group, a sec-butoxy group, a pentyloxy group, an isopentyloxygroup, a neopentyloxy group, a tert-butoxy group, a tert-pentyloxygroup, a 1-methylbutoxy group, a 2-methylbutoxy group, a hexyloxy groupor the like.

The term “haloC₁₋₆ alkoxy group” means the above C₁₋₆ alkoxy groupsubstituted by the same or different halogen atom as defined above. Forexample, a trifluoromethoxy group, a 1,1,1-trifluoroethoxy group, a1,1,2,2-pentafluoroethoxy group or the like can be illustrated.

The term “C₁₋₆ alkylthio group” means a straight-chained or branchedalkylthio group having 1 to 6 carbon atoms such as a methylthio group,an ethylthio group, a propylthio group, an isopropylthio group, abutylthio group, an isobutylthio group, a sec-butylthio group, atert-butylthio group, a pentylthio group, an isopentylthio group, aneopentylthio group, a tert-pentylthio group, a 1-methylbutylthio group,a 2-methylbutylthio group, a hexylthio group or the like.

The term “C₂₋₇ acyl group” means a straight-chained, branched or cyclicacyl group having 2 to 7 carbon atoms such as an acetyl group, apropionyl group, a butyryl group, an isobutyryl group, a pivaloyl group,a hexanoyl group, a cyclohexylcarbonyl group or the like.

The term “C₂₋₇ alkoxycarbonyl group” means a straight-chained, branchedor cyclic alkoxycarbonyl group having 2 to 7 carbon atoms such as amethoxycarbonyl group, an ethoxycarbonyl group, an isopropyloxycarbonylgroup, an isobutylcarbonyl group, an isobutyloxycarbonyl group, acyclohexyloxycarbonyl group or the like.

The term “C₁₋₆ alkoxy (C₂₋₇ acyl) group” means the above C₂₋₇ acyl groupsubstituted by the above C₁₋₆ alkoxy group.

The term “aryl group” means an aromatic hydrocarbon group having 1 to 3rings such as a phenyl group, a naphthyl group or the like,unsubstituted or substituted by a group described below independentlyselected from a group consisting of a halogen atom, a nitro group, aC₁₋₆ alkyl group, a haloC₁₋₆ alkyl group and a C₁₋₆ alkoxy group.

The term “arylcarbonyl group” means a carbonyl group substituted by theabove aryl group, such as a benzoyl group or the like.

The term “aryl (C₁₋₆ alkyl) group” means a C₁₋₆ alkyl group substitutedby the above aryl group. For example, a benzyl group, a 4-methoxybenzylgroup, a 4-methylbenzyl group, a 4-nitrobenzyl group, a 4-chlorobenzylgroup, a phenylethyl group or the like can be illustrated.

The term “arylmethyl group” means a methyl group substituted by theabove aryl group among the above aryl (C₁₋₆ alkyl) group, such as abenzyl group, a 4-methoxybenzyl group, a 4-methylbenzyl group, a4-nitrobenzyl group, a 4-chlorobenzyl group or the like.

The term “arylmethyloxy group” means a group substituted by the abovearylmethyl group which is represented by arylmethyl-O—. For example, abenzyloxy group, a 4-methoxybenzyloxy group, a 4-methylbenzyloxy group,a 4-nitrobenzyloxy group, a 4-chlorobenzyloxy group or the like can beillustrated.

The term “aryl(C₁₋₆ alkoxy) group” means a C₁₋₆ alkoxy group substitutedby the above aryl group, and for example, a group represented byaryl-CH₂—O—, aryl-(CH₂)₂—O—, aryl-(CH₂)₃—O— or the like. A benzyloxygroup, a 4-methoxybenzyloxy group, a 4-methylbenzyloxy group, a4-nitrobenzyloxy group, a 4-chlorobenzyloxy group or the like can beillustrated.

The term “C₁₋₆ alkylsulfonyloxy group” means a sulfonyloxy groupsubstituted by the above C₁₋₆ alkyl group such as a methanesulfonyloxygroup, an ethanesulfonyloxy group or the like.

The term “arylsulfonyloxy group” means a group represented byaryl-SO₂—O— which is substituted by the above aryl group, for example,such as a benzensulfonyloxy group, a 4-methylbenzensulfonyloxy group, a4-nitrobenzensulfonyloxy or the like.

The term “C₁₋₆ acyloxy group” means a group represented by (C₁₋₆acyl)-O—, which substituted by the above C₁₋₆ acyl group.

The term “aryloxy group” means a group represented by aryl-O—, which issubstituted by the above aryl group.

The term “mono(C₁₋₆ alkyl)amino C₁₋₆ alkyl group” means the above C₁₋₆alkyl group substituted by an amino group which is mono-substituted bythe above C₁₋₆ alkyl group.

The term “di(C₁₋₆ alkyl)amino C₁₋₆ alkyl group” means the above C₁₋₆alkyl group substituted by an amino group which is di-substituted by thesame or different above C₁₋₆ alkyl group.

The term “C₃₋₆ cycloalkyloxy group” means a group represented by (C₃₋₆cycloalkyl)-O—, which is substituted by the above C₃₋₆ cycloalkyl group.

The term “C₃₋₆ cycloalkyl (C₁₋₆ alkoxy) group” means a C₁₋₆ alkoxy groupsubstituted by the above C₃₋₆ cycloalkyl group.

The term “heteroC₃₋₆cycloalkyl group” means a cyclic alkyl group having3 to 6 carbon atoms which contains any 1 to 4 hetero atoms selected froma group consisting of an oxygen atom, a sulfur atom and a nitrogen atomin the ring other than the binding position. For example, atetrahydrofuran-3-yl group, a tetrahydropyran-3-yl group, atetrahydropyran-4-yl group or the like can be illustrated.

The term “heteroC₃₋₆cycloalkyloxy group” means a group represented byheteroC₃₋₆cycloalkyl-O— which is substituted by the aboveheteroC₃₋₆cycloalkyl group. For example, a tetrahydrofuran-3-yloxygroup, a tetrahydropyran-3-yloxy group, a tetrahydropyran-4-yloxy groupor the like can be illustrated.

The term “heteroC₃₋₆cycloalkyl (C₁₋₆ alkyl) group” means the above C₁₋₆alkyl group substituted by the above heteroC₃₋₆ cycloalkyl group. Forexample, a tetrahydrofuran-3-ylmethyl group, atetrahydropyran-3-ylmethyl group, a tetrahydropyran-4-ylmethyl group orthe like can be illustrated.

The term “C₂₋₆alkenyl group” means a straight-chained or branchedunsaturated hydrocarbon having 2 to 6 carbon atoms, which has at leastone double bond, for example, a vinyl group, an allyl group or the likecan be illustrated.

The term “C₂₋₆alkynyl group” means a straight-chained or branchedunsaturated hydrocarbon having 2 to 6 carbon atoms, which has at leastone triple bond. For example, an ethynyl group, a propargyl group, a2-butyn-1-yl group or the like can be illustrated.

The term “heteroaryl group” means a 5 to 10-membered aromaticheterocyclic group containing any 1 to 4 hetero atoms selected from agroup consisting of an oxygen atom, a sulfur atom and a nitrogen atom inthe ring other than the binding position or an aromatic heterocyclicgroup consisting of a 6-membered ring fused with a 5 or 6-membered ringcontaining any 1 to 4 hetero atoms selected from a group consisting ofan oxygen atom, a sulfur atom and a nitrogen atom in the ring other thanthe binding position. These aromatic heterocyclic groups areunsubstituted or substituted by a group independently selected from agroup consisting of the following groups: a halogen atom, a nitro group,a C₁₋₆ alkyl group, a haloC₁₋₆ alkyl group and a C₁₋₆ alkoxy group.

As a group forming a prodrug, for example, a protective group introducedinto a hydroxy group or a nitrogen atom which can usually be used in aprodrug, such as a C₂₋₇ acyl group, a C₂₋₇ alkoxycarbonyl group or aC₁₋₆ alkoxy(C₂₋₇ acyl) group can be illustrated.

The present invention is explained in detail as follows. The presentinventors found that as shown in the scheme 1 described below, aglycosylation with a hydroxy-protected α-D-gluco-pyranosylbromide can beconducted using the above general formula (I) as a manufacturingintermediate, without using the reagent containing silver that is theheavy metal which has been reported up to now. Moreover, unlike with themethod using a benzylpyrazole derivative represented by the abovegeneral formula (II), a method for preparing the present invention is anexcellent method that has improved the side reaction which a pyrazolederivative used in the reaction reacts with each other and a nitrogenatom on the pyrazole ring is glycosylated even if a hydroxy-protectedα-D-glucopyranosylhalogen derivative is used. Moreover, by the methodfor manufacturing of the present invention a compound represented by thegeneral formula (IV) can be stereoselectively prepared in extremely highα/β selectivity, and the generation of an unnecessary product can besuppressed. And thus, it is a very excellent method from respect ofmanufacturing cost.

In the formula, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, PG¹, Q¹, and X¹ have thesame meanings as defined above.

Process 1

The glycosylated compound represented by the above general formula (IV)can be prepared by allowing a benzylpyrazole derivative (I) to reactwith a sugar donor represented by the above general formula (III) in aninert solvent, in the presence of a base, usually at 20 to 60° C. As thebase used in the reaction, a metal alkoxide such as potassiumtert-butoxide or a reagent such as potassium carbonate, sodiumcarbonate, cesium carbonate or the like can be illustrated. As thesolvent used in the reaction, for example, an ether solvent such astetrahydrofuran, acetates, dimethylimidazolinone, N,N-dimethylformamide,N-methylpyrrolidone, N,N-dimethylacetamide, a ketone solvent such asacetone, acetonitrile, methylene chloride, 1,2-dichloroethane, or amixture of solvents selected from the same or a mixture of the mixtureand water can be illustrated. It is preferable to use 1 to 1.5 amountsof the sugar donor represented by the above general formula (III) usedin the present reaction against the benzylpyrazole derivative (I). Thereaction time is usually from 1 to 16 hours, varying based on a usedstarting material, solvent and reaction temperature.

Among the obtained compound (IV) in the above scheme 1, aglucopyranosyloxypyrazole derivative represented by the general formula(Aa) or (Ab) which is useful as an agent for the prevention or treatmentof diabetes can be prepared by a method described in scheme 2 as followswith a compound represented by the above formula (IVa)

In the formula, R⁸ is a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group, aC₃₋₆ cycloalkyl(C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkyl) group, aheteroC₃₋₆ cycloalkyl group or a heteroC₃₋₆ cycloalkyl (C₁₋₆ alkyl)group, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X² and Q¹¹ have the same meaningsas defined above.

Process 2-1

The glucopyranosyloxypyrazole derivative represented by the abovegeneral formula (V) can be prepared by leaving R⁷CO— on a pyrazole ring,which is achieved to allow compound (IVa) to react in the presence of abase such as potassium hydrogen carbonate, potassium carbonate, sodiumhydrogen carbonate, sodium carbonate or the like, in a solvent, usuallyat 20 to 80° C. As the solvent used in leaving of R⁷CO— on a pyrazolering, an alcohol solvent such as methanol, ethanol or the like, an ethersolvent such as tetrahydrofuran, acetonitrile, dimethylimidazolinone,N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide,acetone, methylethylketone, water, or a mixture of solvents selectedfrom the same can be illustrated. As for amounts of the base used, it ispreferable to use 0.1 to 1 amounts against the compound represented bythe above general formula (IVa). The reaction time is usually from 2 to24 hours, varying based on a used starting material, solvent andreaction temperature.

Process 2-2

About the compound (IVa), in case that R⁷ is an arylmethyloxy group andPG¹¹ in Q¹¹ is an arylmethyl group, the glucopyranosyloxypyrazolederivative represented by the above general formula (Aa) can be preparedby subjecting the compound (IVa) to catalytic reduction in an alcoholsolvent such as methanol, ethanol or the like, acetates, tetrahydrofuranor a mixture of solvents selected from the same, in the presence ofmetallic catalysts such as palladium, under a hydrogen atmosphere,usually at 20 to 60° C. The reaction time is usually from 2 to 24 hours,varying based on a used starting material, solvent, catalyst andreaction temperature.

Process 2-3

(1) Among a compound represented by the above general formula (V), incase that the protective group PG¹¹ is a benzyl group, debenzylation canbe conducted in the ordinary method. For example, aglucopyranosyloxypyrazole derivative represented by the above generalformula (Aa) can be prepared by subjecting the derivative todeprotection by catalytic reduction in an alcohol solvent such asmethanol, ethanol or the like, acetates, tetrahydrofuran or a mixture ofsolvents selected from the same, in the presence of metallic catalystssuch as palladium on carbon, under a hydrogen atmosphere, usually at 20to 60° C. The reaction time is usually from 2 to 24 hours, varying basedon a used starting material, solvent, catalyst and reaction temperature.

(2) Among the glucopyranosyloxypyrazole derivative represented by theabove general formula (V), in case that the protective group PG¹¹ is abenzoyl group or a pivaloyl group, the glucopyranosyloxypyrazolederivative represented by the above general formula (Aa) can be preparedby subjecting the derivative to deprotection by hydrolysis under a basiccondition, or by solvolysis in an alcohol solvent using a metal alkoxideusually at 20 to 60° C. The reaction time is usually from 2 to 24 hours,varying based on a used starting material, solvent, reaction conditionand kinds of a protective group.

Process 2-4

The glucopyranosyloxypyrazole derivative represented by the abovegeneral formula (VII) can be prepared by subjecting the compound (V) toN-alkylation using an alkylation reagent (VI) represented by the generalformula R⁸—X² in the presence of a base. It is preferable to use 2 to 4amounts of the alkylation reagent against the compound represented bythe above general formula (V) usually at 0 to 60° C., using a metalalkoxide such as potassium tert-butoxide or the like, sodium hydride,potassium carbonate, sodium carbonate, cesium carbonate, sodium amide orthe like, as the base, in N,N-dimethylformamide, N-methylpyrrolidone,N,N-dimethylacetamide, or a mixture of solvents selected from the same.The reaction time is usually from 1 to 12 hours, varying based on a usedstarting material, solvent and reaction temperature. A catalytic amountof sodium iodide or potassium iodide can be optionally used in thepresent N-alkylation.

Process 2-5

(1) Among the compound represented by the above general formula (VII),in case that PG¹¹ is a benzyl group, debenzylation can be conducted inthe ordinary method. For example, the glucopyranosyloxypyrazolederivative represented by the above general formula (Ab) can be preparedby subjecting PG to elimination by catalytic reduction in an alcoholsolvent such as methanol, ethanol or the like, acetates, tetrahydrofuranor a mixture of solvents selected from the same, in the presence ofmetallic catalysts such as palladium on carbon, under a hydrogenatmosphere, usually at 25 to 60° C. The reaction time is usually from 2to 24 hours, varying based on a used starting material, solvent,catalyst and reaction temperature.

(2) Among the glucopyranosyloxypyrazole derivative represented by theabove general formula (VII), in case that PG¹¹ is a benzoyl group or apivaloyl group, the glucopyranosyloxypyrazole derivative represented bythe above general formula (Ab) can be prepared by subjecting PG¹¹ toelimination by hydrolysis under a basic condition, or by solvolysis inan alcohol solvent using a metal alkoxide usually at 20 to 60° C. Thereaction time is usually from 2 to 24 hours, varying based on a usedstarting material, solvent, reaction condition and kinds of a protectivegroup.

Among the obtained compound (IV) in the above scheme 1, theglucopyranosyloxypyrazole derivative represented by the above generalformula (Aa) can be prepared by a method described in the followingscheme 3 with a compound represented by the following formula (IVb)wherein PG¹¹ in Q¹ is an acetyl group.

In the formula, Q¹² is the general formula:

wherein PG¹² is an acetyl group, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have thesame meanings as defined above.

Process 3

The glucopyranosyloxypyrazole derivative represented by the abovegeneral formula (Aa) can be prepared by subjecting compound (IVb) toelimination of R⁷CO— group on a pyrazole ring and PG¹² group at a sugaralcohol group at the same time, in the presence of a base such as ametal alkoxide such as sodium methoxide or the like, potassiumcarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide,lithium hydroxide or the like, in an alcohol solvent such as methanol,ethanol or the like, acetonitrile, an ether solvent such astetrahydrofuran, water or a mixture of solvents selected from the sameat 20 to 80° C. As for amounts of the base used, it is preferable to use0.2 to 7 amounts against the compound represented by the above generalformula (IVb). The reaction time is usually from 2 to 12 hours, varyingbased on a used starting material, solvent and reaction temperature.

The obtained glucopyranosyloxypyrazole derivative represented by thegeneral formula (Aa) or (Ab) in the above scheme 2 or 3 can be led tothe compound represented by the above general formula (A), which has aprodrug forming group at R¹⁰ or P, by prodrug-forming in the methoddescribed in the above Patent Reference 1 or the similar methods.

The 1-acyl-4-benzylpyrazole derivative represented by the above generalformula (I) used as starting materials in the above-mentioned scheme 1can be prepared in the method described in the following scheme 4, forexample, using a benzylpyrazole derivative represented by the followinggeneral formula (VIII) which can be prepared in the method described inthe above Patent References 1 to 6 or the similar methods.

In the formula, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the same meanings asdefined above.

Process 4

By allowing a benzylpyrazol derivative (VIII) to react with (R⁷CO)₂O,R⁷COO—COR⁷⁷ wherein R⁷⁷ is a C₁₋₆ alkyl group, or a reactive functionalderivative represented by the general formula R⁷ COX³ wherein X³ is ahalogen atom, a C₂₋₇ acyloxy group, an arylcarbonyloxy group, a C₁₋₆alkylsulfonyloxy group, a group represented by a formula:

or an arylsulfonyloxy group which may have substitutents selected from agroup consisting of a halogen atom, a nitro group and a C₁₋₆ alkylgroup, in a solvent or without, usually at 0 to 100° C., the1-acyl-4-benzylpyrazole derivative represented by the above generalformula (I) of the present invention can be prepared. As the solventused in the reaction, for example, N,N-dimethylformamide, acetonitrile,methylene chloride, 1,2-dichloroethane or a mixture of solvents selectedfrom the same can be illustrated. As for used amounts of the acidanhydride or the reactive functional derivative used in the presentreaction, it is preferable to use 1 to 3 amounts against the compound(VIII). The reaction time is usually from 1 to 12 hours, varying basedon a used starting material, solvent and reaction temperature. Thepresent reaction can be carried out without a base or an acid. In casethat R⁶ is not a bulky group such as methyl group, ethyl group and thelike, it is more preferable to be carried out in the presence of a baseor an acid. As a base, 1 to 2 amounts of pyridine, triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene, potassiumhydrogen carbonate, potassium carbonate, sodium carbonate, sodiumhydrogen carbonate, cesium carbonate or the like can be illustrated, asan acid, 0.1 to 1.5 amounts of acetic acid or p-tosic acid can beillustrated. On the other hand, in case that R⁶ is a bulky group such asan isopropyl group, an isobutyl group, a sec-butyl group or the like, itis more preferable to be carried out under an acid condition, as anacid, 0.1 to 1.5 amounts of acetic acid or p-tosic acid can beillustrated.

These glucopyranosyloxypyrazole derivatives (A) can be converted intotheir pharmaceutically acceptable salts optionally in the usual way.Examples of these salts include acid addition salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid, sulfuric acid, acetic acid, phosphoric acid and the like, acidaddition salts with organic acids such as formic acid, acetic acid,adipic acid, citric acid, fumaric acid, maleic acid, oleic acid, lacticacid, stearic acid, succinic acid, tartaric acid, propionic acid,butyric acid, oxalic acid, malonic acid, malic acid, carbonic acid,glutamic acid, aspartic acid, methanesulfonic acid, benzenesulfonicacid, p-tolylsulfonic acid and the like, salts with organic amines suchas 2-aminoethanol, piperidine, morpholine, pyrrolidine and the like,inorganic salts such as sodium salt, potassium salt, calcium salt,magnesium salt and the like can be illustrated.

The compound represented by the above general formula (III) used in theglycosylation as described in the above scheme 1 is commerciallyavailable or can be respectively prepared in the method described in“Journal of Chemical Society, pp. 636 to 649 (1959)” or the similarmethod when PG¹ is an acetyl group, a benzoyl group or a pivaloyl groupand X¹ is a chlorine atom, in the method described in “TetrahedronLetters, vol. 30, pp 3081-3084 (1989)” or the similar method when PG¹ isa benzyl group, or in the method described in “Liebigs Annalen derchemie, vol. 1, pp. 41 to 48 (1982)” or the similar method when PG¹ is apivaloyl group and X¹ is a bromine atom. The other compound (III) can beprepared in the similar method as described above

Among the 1-acyl-4-benzylpyrazole derivatives represented by the abovegeneral formula (I) of the present invention, there can be sometautomers (I′) described in scheme as follows. The states change by thedifference of the reaction condition. The 1-acyl-4-benzylpyrazolederivatives (I) of the present invention also include their tautomers(I′).

In the formula, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the same meanings asdefined above.

EFFECT OF THE INVENTION

According to a method for the preparation of the present invention, forexample, the glucopyranosyloxypyrazole derivative represented by theabove general formula (A) or a pharmaceutically acceptable salt thereofwhich is useful as an agent for the prevention or treatment of a diseaseassociated with hyperglycemia such as diabetes, diabetic complications,obesity or the like can be prepared easily and efficiently. Moreoverthough α/β selectivity in the glycosylation is very excellent, it is astereoselective method for preparing, and the glucopyranosyloxypyrazolederivative represented by the above general formula (A) or apharmaceutically acceptable salt thereof can be prepared efficiently andeffectively.

BEST MODE TO PRACTICE THE INVENTION

The present invention is further illustrated in more detail by way ofthe following Examples, however the invention is not limited thereto.

EXAMPLES Reference Example 11-Acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.50 g) was dissolvedin tetrahydrofuran (6.0 g) at room temperature. Acetic anhydride (0.708g) and acetic acid (0.0208 g) was added to the solution successively.After the reaction mixture was stirred at room temperature for 15 hours,the solvent was removed under reduced pressure. The residue was purifiedby column chromatography on silica gel (The product was eluted withdichloromethane at first, and then n-hexane/ethyl acetate=4/1) to give1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.38 g).

¹H-NMR (CDCl₃) δ (ppm) 1.13-1.19 (6H, m), 2.63-2.66 (3H, m), 2.75-2.80(0.4H, m), 2.99-3.04 (0.6H, m), 3.63-3.69 (2H, m), 7.13-7.30 (5H, m),8.26 (0.4H, br-s)

Reference Example 21-Acetyl-4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

1-Acetyl-4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-onewas prepared in a similar manner described in (Reference Example 1)using4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ (ppm): 1.1-1.2 (6H, m), 2.30 (1.2H, s), 2.32 (1.8H, s),2.64 (1.2H, s), 2.65-2.8 (2.2H, m), 2.85-2.95 (0.6H, m), 3.53 (1.2H, s),3.56 (0.8H, s), 5.02 (2H, s), 6.65-6.75 (1H, m), 6.75-6.85 (1H, m), 6.92(0.4H, d, J=8.3 Hz), 6.98 (0.6H, d, J=8.3 Hz), 7.25-7.45 (5H, m), 8.12(0.6H, s), 9.94 (0.4H, s)

Reference Example 34-Benzyl-1,2-dihydro-5-isopropyl-1-propionyl-3H-pyrazol-3-one

4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was dissolvedin tetrahydrofuran (10 mL) at room temperature. Propionic anhydride(1.26 g) and propionic acid (0.012 g) was added to the solutionsuccessively. After the reaction mixture was stirred at room temperaturefor 3 hours, the solvent was removed under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent:dichloromethane/ethyl acetate=1/1) to give4-benzyl-1,2-dihydro-5-isopropyl-1-propionyl-1H-pyrazol-3-one (1.98 g).

¹H-NMR (CDCl₃) δ (ppm): 1.11-1.32 (9H, m), 2.70-2.80 (0.4H, m),2.91-3.16 (2.6H, m), 3.63-3.72 (2H, m) 7.14-7.28 (5H, m) 8.3 (0.4H,br-s)

Reference Example 41-Acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one

4-Benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended inN,N-dimethylformamide (5 mL) at room temperature. In addition, potassiumcarbonate (0.441 g) was added to the suspension, and the mixture wasstirred for 30 minutes. Acetic anhydride (0.570 g) was added to themixture in a dropwise manner at room temperature. The mixture wasstirred at room temperature overnight and at 50° C. for 2 hours. Inaddition, the mixed solution of glacial acetic acid (0.191 g) and water(5.0 g) was added to the reaction mixture under stirring at roomtemperature. After confirming the precipitation of the crystals, water(25 g) was added to the mixture under stirring. The crystals werecollected by filtration, washed with water and dried under reducedpressure to give a white solid of1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.92 g).

¹H-NMR (DMSO-d₆) δ (ppm): 2.41 (3H, s), 2.46 (3H, s), 3.61 (2H, s),7.14-7.18 (3H, m), 7.24-7.28 (2H, m), 11.0 (1H, br)

Reference Example 51-Acetyl-1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

1,2-Dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one(1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at roomtemperature. In addition, potassium carbonate (0.319 g) was added to thesuspension, and the mixture was stirred for 30 minutes. Acetic anhydride(0.412 g) was added to the mixture in a dropwise manner at roomtemperature. The mixture was stirred at room temperature overnight andat 50° C. for 2 hours. In addition, the mixed solution of glacial aceticacid (0.139 g) and water (5.0 g) was added to the reaction mixture understirring at room temperature. After confirming the precipitation of thecrystals, water (25 g) was added to the mixture. The obtained crystalswere collected by filtration, washed with water and dried under reducedpressure to give a white solid of1-acetyl-1,2-dihydro-4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3H-pyrazol-3-one(0.90 g).

¹H-NMR (DMSO-d₆) δ (ppm): 1.22 (6H, d, J=6.2 Hz), 2.40 (3H, s), 2.45(3H, s), 3.52 (2H, s), 4.49-4.54 (1H, m), 6.78-6.81 (2H, m), 7.04-7.06(2H, m), 11.0 (1H, br)

Reference Example 61-Acetyl-4-[(3-fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

4-[(3-Fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one(1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at roomtemperature. Potassium carbonate (0.376 g) was added to the suspension,and the mixture was stirred for 30 minutes. Acetic anhydride (0.486 g)was added to the reaction mixture in a dropwise manner at roomtemperature. The mixture was stirred at room temperature overnight andat 50° C. for 2 hours. The mixture was cooled to room temperature understirring, the mixed solution of glacial acetic acid (0.164 g) and water(5.0 g) was added to the mixture. After confirming the precipitation ofthe crystals, water (25 g) was added to the mixture. The obtainedcrystals were collected by filtration and washed with water. Theobtained wet crystals were dried under reduced pressure to give ayellowish-white solid of1-acetyl-4-[(3-fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one(0.502 g).

¹H-NMR (DMSO-d₆) δ (ppm): 2.16 (3H, s), 2.40 (3H, s), 2.45 (3H, s), 3.58(2H, s), 6.89-6.91 (2H, m), 7.14-7.17 (1H, m), 11.0 (1H, br-s)

Reference Example 71-Benzyloxycarbonyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was dissolvedin N,N-dimethylformamide (5 mL) at room temperature.N-(Benzyloxycarbonyloxy)succinimide (2.42 g) was added to the solution.The mixture was heated to 50° C. and then stirred for 16 hours. Afterthe addition of water (20 mL) and ethyl acetate (20 mL) to the reactionmixture, the aqueous layer was separated, and the organic layer waswashed with water. The obtained organic layer was concentrated underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: ethyl acetate/dichloromethane=1/3 to 1/1) to give1-benzyloxycarbonyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one(1.15 g).

¹H-NMR (DMSO-d₆) δ (ppm): 1.12 (6H, t, J=8.3 Hz), 1.80-2.10 (1H, m),3.31 (2H, br-s), 3.39-3.70 (2H, m), 5.18 (0.4H, br-s), 5.37 (0.6H,br-s), 7.06-7.26 (5H, m), 7.36-7.49 (5H, m), 11.1 (0.6H, br-s), 12.3(0.4H, br-s)

Reference Example 84-Benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

N-Hydroxysuccinimide (1.06 g) was dissolved in tetrahydrofuran (10 g) atroom temperature. Triethylamine (0.936 g) and ethyl chloroformate (1.00g) were added to the solution successively. After stirring the reactionmixture at room temperature for 30 minutes,4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was added tothe mixture at room temperature. After the reaction mixture was stirredat room temperature for 13 hours, the reaction mixture was stirred at50° C. for 6 hours. The insoluble materials were removed, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=4/1) to give4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ (ppm): 1.16-1.20 (6H, m), 1.39-1.49 (3H, m), 2.81-2.94(1H, m), 3.71-3.72 (2H, m), 4.37-4.41 (0.9H, m), 4.52-4.57 (1.1H, m),7.15-7.30 (5H, m), 9.38 (1H, br-s)

Reference Example 94-Benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one

4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.00 g) was dissolvedin tetrahydrofuran (10 mL) at room temperature. A mixed anhydride offormic acid and acetic acid (0.489 g) and acetic acid (0.0140 g) weresuccessively added to the solution. After stirring the reaction mixtureat room temperature for 5 hours, the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: n-hexane:ethyl acetate=4:1) to give4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g).

¹H-NMR (CDCl₃) δ (ppm): 1.19 (6H, d, J=7.5 Hz), 3.00-3.06 (1H, m), 3.63(2H, s), 7.14-7.30 (5H, m), 9.04 (1H, s)

Example 11-Acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.26 g) inacetonitrile (20 mL) were added potassium carbonate (1.01 g) and2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.96 g) understirring at room temperature. In addition, the mixture was heated to 50°C. and stirred for 3 hours. After the completion of the reaction, theinsoluble material was removed by filtration. The filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) togive1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(2.68 g).

¹H-NMR (CDCl₃) δ (ppm): 1.03-1.05 (6H, m), 1.06 (9H, s), 1.12 (9H, s),1.13 (9H, s), 1.19 (9H, s), 2.52-2.59 (4H, m), 3.65-3.76 (3H, m),3.91-3.95 (1H, m), 4.09-4.12 (1H, m), 5.12 (1H, t, J=10 Hz), 5.27-5.30(1H, m), 5.40 (1H, t, J=9.5 Hz), 5.46 (1H, d, J=8.0 Hz), 7.15-7.24 (5H,m)

Example 21-Acetyl-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole

1-Acetyl-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazolewas prepared in a similar manner described in (Example 1) using1-acetyl-4-[(4-benzyloxy-2-methylphenyl)-methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ (ppm): 1.02 (3H, d, J=6.9 Hz), 1.05-1.15 (30H, m), 1.18(9H, s), 2.29 (3H, s), 2.5-2.65 (4H, m), 3.5-3.65 (3H, m), 3.87 (1H, dd,J=12.3 Hz, 5.8 Hz), 4.03 (1H, dd, J=12.3 Hz, 1.5 Hz), 4.95-5.1 (3H, m),5.2-5.3 (1H, m), 5.3-5.4 (2H, m), 6.64 (1H, dd, J=8.5 Hz, 2.4 Hz), 6.8(1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.5 Hz), 7.25-7.4 (3H, m), 7.4-7.45(2H, m)

Example 34-Benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(2.68 g) in methanol (27 mL) was added sodium bicarbonate (0.596 g)under stirring at room temperature. The reaction mixture was stirred atroom temperature for 17 hours. After confirming the completion of thereaction, water was added to the reaction mixture in order toprecipitate the crystals. The crystals were collected by filtration, andthe obtained crystals were washed with water and dried under reducedpressure to give4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(2.45 g).

¹H-NMR (CDCl₃) δ (ppm): 1.06 (9H, s), 1.10-1.17 (33H, m), 2.82-2.90 (1H,m), 3.65 (2H, s), 3.84-3.87 (1H, m), 4.10-4.21 (2H, m), 5.23 (1H, t,J=9.5 Hz), 5.26-5.30 (1H, m), 5.38 (1H, t, J=9.5 Hz), 5.69 (1H, d, J=8.5Hz), 7.11-7.21 (5H, m), 8.74 (1H, br-s)

Example 44-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolewas prepared in a similar manner described in (Example 3) using1-acetyl-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ (ppm): 1.04 (9H, s), 1.05-1.2 (33H, m), 2.27 (3H, s),2.7-2.85 (1H, m), 3.45-3.6 (2H, m), 3.8-3.9 (1H, m), 4.11 (1H, dd,J=12.6 Hz, 4.8 Hz), 4.17 (1H, dd, J=12.6 Hz, 1.8 Hz), 5.0 (2H, s),5.15-5.3 (2H, m), 5.37 (1H, t, J=9.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.64(1H, dd, J=8.4 Hz, 2.8 Hz), 6.77 (1H, d, J=2.8 Hz), 6.83 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Example 54-Benzyl-5-isopropyl-1-propionyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-benzyl-1,2-dihydro-5-isopropyl-1-propionyl-3H-pyrazol-3-one (1.25 g)in acetonitrile (25 mL) were added potassium carbonate (0.951 g) and2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.79 g) understirring at room temperature. In addition, the mixture was heated to 50°C. and stirred for 3 hours. After the completion of the reaction, theinsoluble materials were removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) togive4-benzyl-5-isopropyl-1-propionyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(3.00 g).

¹H-NMR (CDCl₃) δ (ppm): 1.02-1.04 (6H, m), 1.05 (9H, s), 1.12 (9H, s),1.13 (9H, s), 1.20 (9H, s), 1.20-1.21 (3H, m), 2.51-2.59 (1H, m),2.95-3.12 (2H, m), 3.65-3.76 (3H, m), 3.92-3.95 (1H, m), 4.08-4.11 (1H,m), 5.13 (1H, t, J=9.5 Hz), 5.27-5.31 (1H, m), 5.42 (1H, t, J=9.5 Hz),5.50 (1H, d, J=8.0 Hz), 7.15-7.33 (5H, m)

Example 64-Benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-benzyl-5-isopropyl-1-propionyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(3.00 g) in methanol (30 mL) was added sodium bicarbonate (0.654 g)under stirring at room temperature. The reaction mixture was stirred atroom temperature for 17 hours. After confirming the completion of thereaction, water was added to the mixture to precipitate the crystals.The crystals were collected by filtration. The obtained crystals werewashed with water and dried under reduced pressure to give4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(2.67 g).

Example 71-Acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.75 g) inacetonitrile (5 mL) and tetrahydrofuran (3 mL) was added potassiumcarbonate (0.675 g) under stirring at room temperature. After themixture was stirred at 50° C. for 1 hour,1-bromo-2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.27 g) wasadded to the mixture. The mixture was stirred at 50° C. for 6 hours.After the reaction completed, the insoluble materials were removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (eluent:ethyl acetate/n-hexane=1/10 to 1/5) to give1-acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.88 g).

¹H-NMR (CDCl₃) δ ppm: 1.00 (9H, s), 1.13 (9H, s), 1.16 (9H, s), 1.18(9H, s), 2.47 (3H, s), 2.54 (3H, s), 3.60 (2H, s), 3.89-3.92 (1H, m),4.12-4.19 (2H, m), 5.23 (1H, t, J=9.6 Hz), 5.29-5.32 (1H, m), 5.43 (1H,t, J=9.5 Hz), 5.84 (1H, d, J=8.2 Hz), 7.13-7.22 (3H, m), 7.22-7.26 (2H,m)

Example 81-Acetyl-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1-acetyl-1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one(1.00 g) in acetonitrile (5 mL) and tetrahydrofuran (3 mL) was addedpotassium carbonate (0.719 g) under stirring at room temperature. Afterstirring the mixture at 50° C. for 1 hour,2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (2.35 g) was addedto the mixture. The mixture was stirred at 50° C. for 12 hours. Afterthe reaction completed, the insoluble materials were removed byfiltration, and the filtrate was concentrated under reduced pressure.2-Propanol was added to the residue, and the mixture was re-concentratedunder reduced pressure. The residue was recrystallized in the mixedsolvent of water and methanol, the obtained crystals were dried underreduced pressure to give1-acetyl-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(2.19 g).

¹H-NMR (CDCl₃) δ (ppm): 1.01 (9H, s), 1.13 (9H, s), 1.16 (9H, s), 1.18(9H, s), 1.28-1.30 (6H, m), 2.47 (3H, s), 2.54 (3H, s), 3.53 (2H, s),3.89-3.92 (1H, m), 4.12-4.20 (2H, m), 4.46-4.49 (1H, m), 5.23 (1H, t,J=9.7 Hz), 5.29-5.32 (1H, m), 5.43 (1H, t, J=9.4 Hz), 5.84 (1H, d, J=8.2Hz), 6.75-6.77 (2H, m), 7.01-7.03 (2H, m)

Example 91-Acetyl-4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one(0.32 g) in acetonitrile (3 mL) and tetrahydrofuran (1 mL) was addedpotassium carbonate (0.253 g) under stirring at room temperature. Afterstirring the mixture at 50° C. for 1 hour,2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.849 g) was addedto the mixture. The mixture was stirred at 50° C. for 2 hours. After thereaction completed, the insoluble materials were removed by filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent: ethylacetate/n-hexane=1/10 to 1/5) to give1-acetyl-4-[(3-fluoro-4-methyl-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.884 g).

¹H-NMR (CDCl₃) δ (ppm): 1.00 (9H, s), 1.13 (9H, s), 1.16 (9H, s), 1.17(9H, s), 2.20 (3H, s), 2.46 (3H, s), 2.55 (3H, s), 3.56 (2H, s),3.88-3.91 (1H, m), 4.11-4.19 (2H, m), 5.22 (1H, t, J=9.6 Hz), 5.27-5.30(1H, m), 5.43 (1H, t, J=9.5 Hz), 5.83 (1H, d, J=8.2 Hz), 6.74 (1H, d,J=11 Hz), 6.82 (1H, t, J=1.6 Hz), 7.03 (1H, t, J=7.9 Hz)

Example 104-Benzyl-5-methyl-3-(2,3,4,6-tetra-o-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-acetyl-4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.00 g) in methanol (10 mL) was added potassium bicarbonate (0.058 g)under stirring at room temperature. The reaction mixture was stirred atroom temperature for 16 hours. After the precipitation of the crystalsby the addition of a solution of glacial acetic acid (0.034 g) in water(20 mL) at room temperature, the mixture was stirred for 2 hours. Afterthe suspension was stirred under ice-cooling for 1 hour, the crystalswere collected by filtration. The obtained crystals were washed with amixed solution of 2-propanol and n-heptane, and dried under reducedpressure to give4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.90 g).

¹H-NMR (CDCl₃) δ (ppm): 1.05 (9H, s), 1.12 (9H, s), 1.15 (9H, s), 1.18(9H, s), 2.06 (3H, s), 3.62 (2H, s), 3.84-3.88 (1H, m), 4.10-4.21 (2H,m), 5.22-5.31 (2H, m), 5.38 (1H, t, J=9.3 Hz), 5.67 (1H, d, J=8.0 Hz),7.11-7.15 (3H, m), 7.21-7.23 (2H, m)

Example 114-[(4-Isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1-acetyl-4-[(4-isopropoxyphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.00 g) in methanol (10 mL) was added potassium bicarbonate (0.038 g)under stirring at room temperature. The suspension turned into asolution by heating to reflux, and the mixture was stirred for further 2hours. After confirming the completion of the reaction, a solution ofglacial acetic acid (0.022 g) in water (10 mL) was added to the mixtureat 60° C. to precipitate the crystals. The suspension was cooled to roomtemperature, and stirred under ice-cooling for 1 hour. The crystals werecollected by filtration, and the obtained crystals were washed with amixed solution of 2-propanol and n-heptane, and dried under reducedpressure to give4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.890 g).

¹H-NMR (CDCl₃) δ (ppm): 1.05 (9H, s), 1.12 (9H, s), 1.15 (9H, s), 1.18(9H, s), 1.28-1.30 (6H, m), 2.06 (3H, s), 3.54 (2H, s), 3.83-3.87 (1H,m), 4.11-4.20 (2H, m), 4.44-4.49 (1H, m), 5.22-5.31 (2H, m), 5.38 (1H,t, J=9.4 Hz), 5.67 (1H, d, J=8.2 Hz), 6.73-6.76 (2H, m), 7.02-7.04 (2H,m), 8.69 (1H, br-s)

Example 124-[(3-Fluoro-4-methylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-acetyl-4-[(3-fluoro-4-methylphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.75 g) in methanol (5 mL) was added potassium bicarbonate (0.030 g)under stirring at room temperature. The mixture was stirred at 50° C.for 3 hours. To the mixture was added glacial acetic acid (0.022 g) at60° C., and the resulting mixture was concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (eluent: ethyl acetate/n-hexane=1/5) to give4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.610 g).

¹H-NMR (CDCl₃) δ (ppm): 1.05 (9H, s), 1.12 (9H, s), 1.15 (9H, s), 1.18(9H, s), 2.07 (3H, s), 2.20 (3H, s), 3.57 (2H, s), 3.85-3.88 (1H, m),4.12-4.20 (2H, m), 5.23-5.30 (2H, m), 5.38 (1H, t, J=9.4 Hz), 5.60 (1H,d, J=8.1 Hz), 6.74-6.77 (1H, m), 6.81-6.83 (1H, m), 7.02 (1H, t, J=7.9Hz)

Example 131-Benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-benzyloxycarbonyl-4-benzyl-5-isopropyl-1,2-dihydro-3H-pyrazol-3-one(0.16 g) in acetonitrile (5 mL) were added potassium carbonate (0.0757g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.278 g)successively under stirring at room temperature. In addition, themixture was stirred at 50° C. for 4 hours. The reaction mixture waspoured into water, and the resulting mixture was extracted with diethylether. The organic layer was washed with brine and dried over anhydrousmagnesium sulfate. The insoluble materials were removed by filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent: ethylacetate/n-hexane=1/6) to give1-benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(0.228 g).

¹H-NMR (CDCl₃) δ (ppm): 1.05-1.20 (42H, m), 2.55-2.70 (1H, m), 3.40-3.50(1H, m), 3.70 (1H, d, J=16.7 Hz), 3.74 (1H, d, J=16.7 Hz), 3.87 (1H, dd,J=12.3, 6.1 Hz), 3.97 (1H, dd, J=12.3, 1.7 Hz), 4.85-4.95 (1H, m),5.11-5.17 (2H, m), 5.22-5.25 (1H, m), 5.41 (1H, d, J=12.1 Hz), 5.45 (1H,d, J=12.1 Hz), 7.05-7.15 (2H, m), 7.15-7.30 (3H, m), 7.35-7.55 (5H, m)

Example 144-Benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(0.228 g) in methanol (5 mL) was added 10% palladium on carbon (50% wet:0.40 g). In addition, the mixture was stirred under a hydrogenatmosphere at room temperature for 13 hours. The insoluble materialswere removed by filtration through Celite®, and the filtrate wasconcentrated under reduced pressure to give4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.186 g).

Example 154-Benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one(0.100 g) in acetonitrile (3 mL) were added potassium carbonate (0.0575g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.211 g)successively under stirring at room temperature. In addition, themixture was stirred at 50° C. for 2.5 hours. The mixture was poured intowater, and the resulting mixture was extracted with diethyl ether. Theorganic layer was washed with brine and dried over anhydrous magnesiumsulfate. The insoluble materials were removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: ethylacetate/n-hexane=1/8 to 1/5 to 1/4) to give4-benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.15 g).

¹H-NMR (CDCl₃) δ (ppm): 1.05-1.10 (15H, m), 1.12 (9H, s), 1.13 (9H, s),1.18 (9H, s), 1.44 (1H, t, J=7.1 Hz), 2.62-2.68 (1H, m), 3.55-3.65 (1H,m), 3.75 (2H, s), 3.97 (1H, dd, J=12.4, 5.3 Hz), 4.05 (1H, dd, J=12.4,1.8 Hz), 4.40-4.55 (1H, m), 5.11-5.15 (1H, m), 5.25-5.37 (3H, m),7.12-7.26 (5H, m)

Example 164-Benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(0.15 g) in methanol (3 mL) was added sodium bicarbonate (0.032 g) understirring at room temperature. The mixture was stirred at roomtemperature for 12 hours. In addition, to the mixture was addedpotassium carbonate (0.053 g), and the mixture was stirred for 2 hours.The reaction mixture was poured into water to precipitate the solid. Thesolids were collected by filtration. The obtained solids were washedwith water and dried under reduced pressure to give4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.098 g).

Example 174-Benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To solution of4-benzyl-1,2-dihydro-1-formyl-5-isopropyl-3H-pyrazol-3-one (1.07 g) inacetonitrile (20 mL) were added potassium carbonate (0.905 g) and2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.65 g) understirring at room temperature. In addition, the mixture was heated to 50°C. and stirred for 1 hour. After the reaction completed, the insolublematerials were removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) togive4-benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(1.49 g).

¹H-NMR (CDCl₃) δ (ppm): 1.09-1.13 (33H, m), 1.16 (9H, s), 2.62-2.68 (1H,m), 3.59 (1H, br-s), 3.69-3.81 (2H, m), 3.95-3.98 (1H, m), 4.05-4.07(1H, m), 5.11-5.32 (4H, m), 7.09-7.13 (2H, m), 7.20-7.29 (3H, m), 9.03(1H, s)

Example 184-Benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-benzyl-1-formyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.49 g) in methanol (15 mL) was added sodium bicarbonate (0.337 g)under stirring at room temperature. The reaction mixture was stirred atroom temperature for 11 hours. After confirming the completion of thereaction, water was added to the mixture to precipitate the crystals.The crystals were collected by filtration, and the obtained crystalswere washed with water and dried under reduced pressure to give4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole(1.40 g).

INDUSTRIAL APPLICABILITY

According to a method for the preparation of the present invention,glucopyranosyloxypyrazole derivatives, for example, theglucopyranosyloxypyrazole derivative represented by the above generalformula (A) or a pharmaceutically acceptable salt thereof, which areuseful as agents for the prevention or treatment of a disease associatedwith hyperglycemia such as diabetes, diabetic complications, obesity orthe like can be easily and efficiently prepared, the present inventionis extremely useful as a method for preparing the pharmaceuticalcompounds represented by the above general formula (A).

1. A method for preparing a glucopyranosyloxypyrazole derivative represented by the general formula:

wherein Q¹¹ is a group represented by the general formula:

in which PG¹¹ is an arylcarbonyl group, a pivaloyl group or an arylmethyl group, and R¹, R², R³, R⁴ and R⁵ may be the same or different, each of them is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a haloC₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group, a C₃₋₆ cycloalkyloxy group, a C₃₋₆ cycloalkyl(C₁₋₆ alkoxy)group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a haloC₁₋₆ alkoxy group, an aryl group, an aryloxy group, a heteroaryl group, an aryl(C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkoxy) group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a heteroC₃₋₆ cycloalkyl group, a heteroC₃₋₆ cycloalkyloxy group, a heteroC₃₋₆ cycloalkyl(C₁₋₆ alkyl)group, a C₁₋₆ alkoxy group substituted by an amino group which is mono-substituted by a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group substituted by an amino group which is di-substituted by a C₁₋₆ alkyl group, and R⁶ is a C₁₋₆ alkyl group, a haloC₁₋₆ alkyl group or a C₃₋₆ cycloalkyl group, which comprises allowing a benzylpyrazole derivative represented by the general formula:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ have the same meanings as defined above, and R⁷ is a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or an arylmethyloxy group to react with a compound represented by the general formula:

in which PG¹¹ has the same meaning as defined above, and X¹ is a bromine atom or a chlorine atom in the presence of a base selected from the group consisting of potassium tert-butoxide, potassium carbonate, sodium carbonate and cesium carbonate to yield a glucopyranosyloxypyrazole derivative represented by the general formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have the same meanings as defined above, and subsequently removing R⁷ CO— on the pyrazole ring. 